Since parasite proteases, and in particular cysteine proteases, are key molecules for a wide variety of parasites, these enzymes are attractive targets for chemotherapy. Structure-based or rational drug design is a new and promising strategy to develop antiparasitic drugs. Three target proteases were selected: a cathepsin L-like cysteine protease from Brugia pahangi third-stage larvae, a cathepsin L-like and a cathepsin B-like cysteine protease from Leishmania major. Based on known crystal structures of cysteine proteases homology enzyme models were built for the target proteases using the programs InsightII (Biosym Technologies, San Diego, CA) and MidasPlus (UCSF). The models were then used to search the Available Chemicals Directory (ACD, a total of about 150,000 compounds) for potential protease inhibitors with the computational software DOCK 3.5 (UCSF) using contact and forcefield scoring. The top 5% for each scoring method was saved and visually examined for size and interactions within the active site. In order to find new lead inhibitors, the most promising compounds (about 0.05%) were selected to be tested in vitro. So far, five lead compounds with Ki values below 10 NM were found for the Leishmania cathepsin B-like enzyme.